The treatment of castration-resistant prostate cancer (CRPC) still faces many challenges. Docetaxel is a chemotherapeutic drug commonly used in CRPC patients. However, docetaxel-based chemotherapy usually causes docetaxel resistance, partially due to the resistance of CRPC cells to docetaxel-induced apoptosis. Here, we report that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) inhibits docetaxel-induced apoptosis of prostate cancer cells, including androgen-independent prostate cancer cells. USP33 is overexpressed in prostate cancer cells and tissues. We found that knockdown or knockout of USP33 enhanced docetaxel-induced apoptosis of prostate cancer cells, accompanied by increased phosphorylation of the cJUN NH2-terminal kinase (JNK). After blocking docetaxel-induced JNK activation using the JNK inhibitor SP600125 or siRNA targeting JNK, the USP33 knockout-enhanced apoptosis was reversed. Furthermore, we found that USP33 could interact with the phosphatase DUSP1 to negatively regulate the activation of JNK, while USP33 knockdown promoted the proteasomal degradation of DUSP1. Mechanistically, we found that USP33 could inhibit the Lys48 (K48)-linked polyubiquitination of DUSP1. More importantly, DUSP1 overexpression could reverse the USP33 knockdown-induced JNK activation and apoptosis in docetaxel-treated prostate cancer cells. Therefore, USP33 overexpression in prostate cancer may contribute to docetaxel resistance by inhibiting the degradation of its partner DUSP1, leading to impaired JNK activation and apoptosis. Our study suggests that USP33-DUSP1-JNK may be a key signalling module mediating the docetaxel resistance of CRPC, indicating that USP33 is a potential novel therapeutic target in CRPC.

Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

The landscape and characteristics of circulating exosomal messenger RNAs (emRNAs) are poorly understood, which hampered the accurate detection of circulating emRNAs. Through comparing RNA sequencing data of circulating exosomes with the corresponding data in tissues, we illustrated the different characteristics of emRNAs compared to tissue mRNAs. We then developed an improved strategy for emRNA detection based on the features of circulating emRNAs. Using the optimized detection strategy, we further validated prostate cancer (PCa) associated emRNAs discovered by emRNA-seq in a large cohort of patients and identified emRNA signatures for PCa screening and diagnosis using logistic regression analysis. The receiver operating characteristic curve (ROC) analysis showed that the circulating emRNA-based screening signature yielded an area under the ROC curve (AUC) of 0.948 in distinguishing PCa patients from healthy controls. The circulating emRNA-based diagnostic signature also showed a great performance in predicting prostate biopsy results (AUC: 0.851). In conclusion, our study developed an optimized emRNA detection strategy and identified novel emRNA signatures for the detection of PCa.

Background: There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. Methods: Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. Results: Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). Conclusions: We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

Objective: To investigate the application of virtual reality training in vesicourethral anastomosis during robot-assisted radical prostatectomy (RARP). Methods: Three certified robotic urologists who underwent virtual reality training were enrolled in the study group. The other three without training were enrolled in the control group. Parameters were recorded before and after the training. Then a total of 18 patients un-dergoing RARP were enrolled and randomized assigned to receive anastomosis procedures with certified urologists who either obtained or did not obtain training. The quality of the anastomosis was evaluated. Results: For the virtual training evaluation, the overall score was significantly improved from 65.0 +/- 10.8 to 92.7 +/- 3.5 (p=0.014); the time of anastomosis was shortened; the economy of motion improved; instrument collisions decreased after training (p<0.05). Besides, the effec-tiveness of the virtual training was evaluated in the 18 real anastomosis procedures which were completed either by three urologists with training or three urologists without training. Most intriguingly, the average time of anastomosis was shortened from 40.0 +/- 12.4 min to 25.1 +/- 7.1 min (p=0.015). The parameters including time of operation, creatinine level of drainage, postoperative hospital stay and duration of catheter drainage were comparable before and after training. Two leakages, which were observed in procedures by doctors without training, needed salvage sutures by a senior doctor. Conclusions: Virtual reality training enabled surgeons to become quickly familiar with robotic system manipulation, improved their skills for vesicourethral anastomosis and shortened the learning curve, thus helping them operate with high efficacy and quality. (C) 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Purpose: The aim of this study was to investigate the value of dual-phase ^99mTc-MIBI SPECT/CT in the differential diagnosis between benign and malignant enhancing solid renal tumors. Patients and Methods: Totally, 180 patients were imaged with dual-phase ^99mTc-MIBI SPECT/CT, which was performed 30 minutes and 90 minutes after ^99mTc-MIBI administration. Among them, 147 patients with 148 histologically proved solid renal tumors met the selection criteria and were included for the final analysis. Relative quantification was performed by measuring the radioactive uptake ratio of tumor to the normal renal parenchymal background for both early and delayed images. Results: Benign renal tumors (4 renal oncocytomas and 8 lipid-poor angiomyolipomas) demonstrated a significantly higher early relative uptake value (ERUV) and delayed relative uptake value (DRUV) than malignant renal tumors (n = 136; both P < 0.0001). The ERUV cutoff value of 0.53 helped to differentiate benign from malignant renal tumors, with sensitivity of 100%, specificity of 94.8%, and accuracy of 95.3% for the diagnosis of benign renal tumors. The DRUV cutoff value of 0.50 helped to differentiate benign from malignant renal tumors, with sensitivity of 100%, specificity of 96.3%, and accuracy of 96.6% for the diagnosis of benign renal tumors. There was no statistically significant difference between the efficacy of ERUV and DRUV in the differential diagnosis between benign and malignant renal tumors (P = 0.5). The efficacies of ERUV and DRUV were all significantly higher than the retention index (both P < 0.0001). Conclusions: Both early and delayed phase ^99mTc-MIBI SPECT/CT are helpful for distinguishing benign renal oncocytoma and lipid-poor angiomyolipoma from malignant renal tumors, and the delayed phase imaging tends to show higher diagnostic accuracy.